EP3017818A1 - Composition pharmaceutique comprenant des derives de l'aminobenzenesulfone pour le traitement des maladies associées à la démyélinisation des neurones - Google Patents

Composition pharmaceutique comprenant des derives de l'aminobenzenesulfone pour le traitement des maladies associées à la démyélinisation des neurones Download PDF

Info

Publication number
EP3017818A1
EP3017818A1 EP15193093.0A EP15193093A EP3017818A1 EP 3017818 A1 EP3017818 A1 EP 3017818A1 EP 15193093 A EP15193093 A EP 15193093A EP 3017818 A1 EP3017818 A1 EP 3017818A1
Authority
EP
European Patent Office
Prior art keywords
composition
formula
compound
alkyl
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP15193093.0A
Other languages
German (de)
English (en)
Other versions
EP3017818B1 (fr
Inventor
Yunil Lee
Kiyoung Chang
Sangchul Park
Sungchun Cho
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Samsung Electronics Co Ltd
Original Assignee
Samsung Electronics Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Samsung Electronics Co Ltd filed Critical Samsung Electronics Co Ltd
Publication of EP3017818A1 publication Critical patent/EP3017818A1/fr
Application granted granted Critical
Publication of EP3017818B1 publication Critical patent/EP3017818B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a pharmaceutical composition for treating a disease associated with demyelination, a method of accelerating remyelination of neuron cells in a mammal, including humans, by using the pharmaceutical composition, and a method of treating a disease associated with demyelination of neuron cells in a mammal.
  • a demyelinating disease is a disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction causes deficiency in sensation, movement, cognition, or other functions depending on which nerves are affected.
  • the demyelinating disease may include diseases affecting the central nervous system and peripheral nervous system.
  • Demyelinating diseases of the peripheral nervous system include Guillain-Barre Syndrome and Charcot Marie Tooth (CMT) diseases.
  • Demyelinating diseases of the central nervous system include multiple sclerosis.
  • ascorbic acid is a known effective treatment of peripheral neuropathy. However, there is a demand for alternative methods of treating these disorders.
  • a pharmaceutical composition for use in treating a disease associated with demyelination of neurons in a mammal Further provided is a pharmaceutical composition for use in accelerating remyelination or suppressing demyelination of neurons in a mammal.
  • a pharmaceutical composition for use in treating a disease associated with demyelination of neurons in a mammal includes a compound represented by Formula 1; or a pharmaceutically acceptable salt or solvate of the pharmaceutical composition.
  • the C1-C6 alkyl may be linear, for example, a linear C1-C3 alkyl group.
  • R 1 and R 2 are each independently H, and R 3 is 4-aminophenyl to provide dapsone (DDS).
  • R 1 and R 2 are each independently H, and R 3 is 4-acetylaminophenyl, providing mono N-acetyldapsone (MADDS).
  • the heteroaryl having 3- to 8-membered cyclic atoms may be a pyridyl.
  • R 3 may be -NR 6 R 7 , in which R 6 is H, and R 7 is a 6-membered nitrogen-containing ring (e.g., pyridine).
  • R 1 and R 2 may together constitute and R 3 may be a pyridinyl-NH-, in which R 6 may be H, and R 7 may be a pyridinyl.
  • R 1 and R 2 may together constitute and R 3 may be providing sulfasalazine (SSZ).
  • R 1 and R 2 are both H; and R 3 is acetyl-NH-, providing sulfacetamide (SCM).
  • the compound may be in the form of a pharmaceutically acceptable salt of any of the foregoing compounds of formula 1.
  • the salt may include acid addition salts that are commonly used in the field of pharmaceuticals including salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid; and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid, or trifluoroacetic acid.
  • examples of the salt may include common metal salts, for example, salts derived from metals such as lithium, sodium, potassium, magnesium,
  • the compound may be in the form of a solvate of formula 1.
  • solvate refers a complex that is constituted of at least one solute molecule, that is, a compound represented by Formula 1 or a pharmaceutically acceptable salt of the compound; and at least one solvent molecule.
  • the solvate may be, for example, a complex formed with water, methanol, ethanol, isopropanol, or acetic acid.
  • the compound may be in the form of a stereoisomer of the compound.
  • the stereoisomer include all types of stereoisomers such as enantiomers and diastereomers.
  • the compound may be in the stereoisomerically pure form of a stereoisomer or a mixture of at least two stereoisomers, for example, a racemic mixture. Isolation of a specific stereoisomer may be performed by using one of the known methods in the art.
  • alkyl denotes a linear or branched monovalent saturated hydrocarbon group. Unless defined otherwise, the alkyl group generally includes 1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbon atoms.
  • the alkyl group may include, for example, methyl, ethyl, propyl (e.g., n-propyl or iso-propyl), butyl (e.g., n-butyl, iso-butyl, or t-butyl), pentyl (e.g., n-pentyl, iso-pentyl, and neopentyl), and n-hexyl.
  • aryl denotes an aromatic hydrocarbon group having a monocyclic or a polycyclic ring.
  • the polycyclic aromatic hydrocarbon group may include one having a fused ring (e.g., naphthalene) and/or a non-fused ring (e.g., biphenyl).
  • the polycyclic aromatic hydrocarbon group may have two, three, or four rings. Unless defined otherwise, the aryl group may generally have 3 to 8, 4 to 7, 5 to 7, 5 to 6, or 6 carbon atoms on the ring.
  • the aryl group may include, for example, a phenyl.
  • heteroaryl denotes a monovalent aromatic group having at least one heteroatom selected from the group consisting of N, O, and S as a ring-constituting member.
  • the heteroaryl group may have a monocyclic or polycyclic structure.
  • the polycyclic structure may have, for example, two, three, or four condensed rings.
  • the heteroaryl group may generally include 3 to 8, 4 to 7, 5 to 7, 5 to 6, or 6 carbon atoms on the ring.
  • the heteroaryl group may include one, two, or three heteroatoms.
  • the heteroaryl group may include, for example, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, furanyl, thiazolyl, oxazolyl, iso-oxazolyl, triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, or isothiazolyl.
  • the compound of Formula 1 may be dapsone (4,4'-diaminodiphenylsulfone, DDS), N-acetyldapsone (NADDS), sulfasalazine (2-hydroxy-5-[(E)-2- ⁇ 4-[pyridin-2-yl)sulfamoyl]phenyl ⁇ diazen-2-yl]benzoic acid, SSZ), or sulfacetamide (N-[(4-aminophenyl)sulfonyl]acetamide, SCM).
  • DDS diaminodiphenylsulfone
  • NADDS N-acetyldapsone
  • sulfasalazine (2-hydroxy-5-[(E)-2- ⁇ 4-[pyridin-2-yl)sulfamoyl]phenyl ⁇ diazen-2-yl]benzoic acid
  • SSZ sulfacetamide
  • SCM
  • Dapsone is an antibacterial agent that is most commonly used in combination with rifampicin and clofazimine as a multidrug therapy (MDT) for the treatmant of leprosy cuased by Mycobacterium leprae.
  • Dapsone is industrially usable as a topical and oral formula.
  • a trade name of the topical dapsone is ACZONETM, and a 5% gel type of the topical dapsone is available from Allergan. Dapsone was first synthesized by Fromm and Wittmann in 1908.
  • NADDS is a metabolite of DDS, and at least one of two amino groups of DDS may be acetylated to synthesize NADDS.
  • MADDS an acetylated compound of one of the two amino groups of DDS.
  • Sulfasalazine brand name Azulfidine in the U.S., Salazopyrin and Sulazine in Europe and Hong Kong
  • Sulfasalazine is a sulfa drug, a derivative of mesalazine, and is formed by combining sulfapyridine and salicylate with an azo bond.
  • Sulfasalazine is used in the treatment of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease.
  • IBD inflammatory bowel disease
  • sulfasalazine is used in the treatment of RA and used in other types of inflammatory arthritis (e.g., psoriatic arthritis) where it has a beneficial effect.
  • U.S. Patent 2,396,145 discloses, for example, a synthesis method of the sulfasalazine.
  • a pharmaceutically acceptable derivative of sulfasalazine may be synthesized by using a method known in the art.
  • Sulfacetamide is a sulfonamide antibiotic.
  • a sulfacetamide 10% topical lotion available in the trade names Klaron or Ovace, is approved for the treatment of acne and seborrheic dermatitis.
  • Synthesis of sulfacetamide may be performed according to Reaction Scheme 2. In the last process of Reaction Scheme 2, an N 4 -acetyl group is selectively removed by alkali hydrolysis.
  • the compound may be synthesized during a synthesis process of sulfonamide or its derivative.
  • the compound may be, for example, synthesized according to Reaction Scheme 3.
  • acetanilide (1) which is a starting material, is commercially available.
  • the acetanilide (1) is reacted with chlorosulfonic acid while heating the reaction solution (e.g., at a temperature of about 70°C to about 80°C) to synthesize 4-acetamidobenzenesulfonyl chloride (2).
  • the 4-acetamidobenzenesulfonyl chloride (2) is reacted with R 6 R 7 NH while heating the reaction solution (e.g., at a temperature of about 70°C to about 80°C) to synthesize Compound 3.
  • N 4 -acetyl group is hydrolyzed by incubating Compound 3 under an alkali condition to obtain Compound 4.
  • Compound 4 is reacted with Compound 5 to be linked through azo coupling (in this case, R 1 and R 2 may together form or to be acylated to synthesize Compound 6.
  • a disease associated with demyelination of neurons is a disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves, which, in turn, causes deficiency in sensation, movement, cognition, or other functions depending on which nerves are involved.
  • the disease may include diseases affecting the central nervous system (also, referred to as “central nervous system demyelinating diseases”) and peripheral nervous system (also, referred to as “peripheral nervous system demyelinating diseases”).
  • the central nervous system demyelinating diseases include multiple sclerosis, Devic's disease, inflammatory demyelinating diseases, central nervous system neuropathies like those produced by Vitamin B12 deficiency, myelopathies like Tabes dorsalis, leukoencephalopathies like progressive multifocal leukoencephalopathy, leukodystrophies, or a combination thereof.
  • the peripheral nervous system demyelinating diseases include Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory dymeylinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot Marie Tooth (CMT) disease, copper deficiency, progressive inflammatory neuropathy, or a combination thereof.
  • the diseases may be multiple sclerosis, Guillain-Barre syndrome, CMT, or a combination thereof.
  • the CMT may be a CMT1A sub-type, CMT1 E sub-type, or CMT3 sub-type.
  • the diseases may be caused by overexpression of peripheral myelin protein 22 (PMP22).
  • PMP22 is a protein which in humans is encoded by the PMP22 gene.
  • the integral membrane protein encoded by this gene is a hydrophobic, tetraspan glycoprotein expressed mainly in Schwann cells and is a major component of compact myelin in the peripheral nervous system.
  • PMP22 has been known to interact with myelin protein zero.
  • Various mutations of the gene are causes of CMT1A, Dejerine-Scottas disease, and hereditary neuropathy with liability to pressure palsy (HNPP).
  • CMT1A is the most common form of the disease, comprising at least 60% of all CMT patients.
  • CMT1A is caused by a duplication of the PMP22 gene on Chromosome 17. Instead of having two copies of the gene, the chromosome may have three copies, two on one chromosome and one on the other chromosome.
  • the compound of Formula 1 or pharmaceutical composition comprising same may be administered to any mammal in need thereof.
  • the mammal may be a human.
  • the mammal may have demyelinated neurons and/or a disease associated with demyelination.
  • the composition may further include a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier denotes a material that is used in combination with an active ingredient, that is, generally, an inert material, to help application of the active ingredient.
  • the carrier may include, in general, a pharmaceutically acceptable excipient, additive, or diluent.
  • the carrier may include at least one selected from the group consisting of a filler, a binder, a disintegrant, a buffer, a preservative, an antioxidant, a lubricant, a flavoring agent, a thickener, a coloring agent, an emulsifier, a suspending agent, a stabilizer, and an isotonic agent.
  • the composition may include the compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof, at a "therapeutically effective dose".
  • therapeutically effective dose denotes a sufficient dose that produces a therapeutic effect when administered to a subject in need of treatment.
  • treatment denotes treatment of a disease or medical condition, for example, a disease associated with demyelination, of a subject such as a mammal, including humans, and the meaning of treatment is the following: (a) ameliorating the disease or medical condition such as by eliminating or causing regression of the disease or medical condition of a patient; (b) suppressing the disease or medical condition such as by slowing or arresting the development of the disease or medical condition of a patient; or (c) alleviating a symptom of the disease or medical condition of a patient.
  • the "effective dose” may be appropriately selected by one of ordinary skill in the art.
  • the "effective dose” may be in a range of about 0.01 mg to about 10,000 mg, 0.1 mg to about 1000 mg, about 1 mg to about 100 mg, about 0.01 mg to about 1000 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, or about 0.01 mg to about 1 mg.
  • the composition may be prepared for oral administration or parenteral administration including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.
  • the composition may be formulated into various forms such as tablets, capsules, aqueous solutions, or suspensions.
  • an excipient such as lactose or corn starch and a lubricant such as magnesium stearate may be added thereto in general.
  • lactose and/or dried corn starch may be used as a diluent.
  • active ingredients may be attached to an emulsifier and/ or a suspending agent.
  • a predetermined sweetening agent and/or a flavoring agent may be added to the composition.
  • a sterilized solution of the active ingredients is generally prepared, and the pH of the solution needs to be appropriately adjusted and buffered.
  • the total concentration of solutes needs to be controlled to render the preparation isotonic.
  • the composition may be formulated in the form of an aqueous solution including a pharmaceutically acceptable carrier such as salt water at a pH of 7.4.
  • the solution may be administered to intramuscular or intraneural blood flow of a patient by local bolus injection.
  • the compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof may have effects of suppressing demyelination or recovering demyelinated neurons by remyelinating neurons.
  • the composition may be used in combination with at least one other treatment agent for treating a disease associated with demyelination.
  • the composition may be used without active ingredients for treating a disease associated with demyelination other than the compound of Formula 1 or a pharmaceutically acceptable salt or solvate of the compound of Formula 1.
  • a method of accelerating remyelination or suppressing demyelination of neurons in a mammal including administering a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof to the mammal at an effective dose to accelerate remyelination:
  • the compound of Formula 1 or salt or solvate thereof may be administered to a subject.
  • the "effective dose to accelerate remyelination" is administered to the subject in need of remyelination, the term denotes a sufficient dose that produces a remyelination effect.
  • a method of treating a disease associated with demyelination of neurons in a mammal including accelerating remyelination of neurons by administering a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof to the mammal with a disease associated with demyelination of neurons at a therapeutically effective dose:
  • a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof a therapeutically effective dose
  • a disease associated with demyelination a disease associated with demyelination
  • the administration may refer to administration of the composition including the "compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof”.
  • the route of the administration may be oral, parenteral, or local administration.
  • An administration dose may vary depending on the condition of a patient, an administration route, and a doctor's decision.
  • An effective administration dose may be inferred by a dose-response curve derived from an in vitro or animal model test system.
  • a ratio and a concentration of the compound of an embodiment in the composition to be administrated may be determined according to chemical characteristics, an administration route, and a therapeutic administration dose.
  • the dose may be administered to a subject, for example, at an effective dose of about 1 ⁇ g/kg to about 1 g/kg per day, or about 0.1 mg/kg to about 500 mg/kg per day.
  • the dose may be changed depending on an age, sensitiveness, or symptoms of the subject.
  • SH-SY5Y cells were inoculated at a concentration of 10 5 cells/ml in each well of a 12-well plate including 2 ml of a DMEM medium containing 10% FBS, 100 units/ml of penicillin, and 100 units/ml of streptomycin and incubated until the cell density was about 60% to about 65% in a 5% CO 2 incubator at 37°C. Then, dapsone (4,4'-diaminodiphenylsulfone, DDS) (available from Sigma), MADDS (available from Sigma), SSZ (available from Sigma), and SCM (available from Sigma) were respectively added to the wells at various concentrations and incubated for 24 hours under the same conditions.
  • DDS dapsone (4,4'-diaminodiphenylsulfone, DDS)
  • MADDS available from Sigma
  • SSZ available from Sigma
  • SCM available from Sigma
  • Vitamin C (ascorbic acid, AA) (available from Sigma) was used as the positive control group. Vitamin C is known as having an effect of treating peripheral neuropathy by using a cAMP modulator.
  • SH-SY5Y cells are a human-derived cell line used in scientific research. The original cell line, SK-N-SH from which SH-SY5Y cells were subcloned, was isolated from a bone marrow biopsy taken from a four year-old female with neuroblastoma. SH-SY5Y cells are often used as in vitro models of neuronal function and differentiation. The SH-SY5Y cells used herein have been modified to consistently overexpress the human PMP22 gene by lentiviral mediated integration of PMP22 into a chromosome.
  • the SH-SY5Y cells were washed with phosphate buffered saline (PBS), and a lysis solution, 0.5% Triton X-100, in PBS was added thereto. Then, cells were collected using a scraper, left in ice for 30 minutes, and then, the cells were disrupted. Using a bicinchoninic acid (BCA) protein assay, the amount of protein in each sample was normalized to 1 ug/ul. SDS-PAGE (Invitrogen) was performed on the sample, and then Western blotting was performed with rabbit anti-PMP22 (Novus biological) and rabbit anti-actin (Sigma) primary antibodies, and an anti-rabbit secondary antibody.
  • BCA bicinchoninic acid
  • FIGS. 1A and 1B illustrate the results of ⁇ -PMP22 gene expression analysis of SH-SY5Y cells in the presence of DDS measured by Western blotting.
  • FIG. 1A is an image of the Western blot
  • FIG. 1B illustrates the results in a graph of intensities or densities of each band of the Western blot measured by using an Image J program.
  • "Mock” represents a non-treatment group
  • "DMSO” represents a control group which is treated with the solvent DMSO instead of DDS
  • DDS represents a test performed with DDS added to DMSO at predetermined concentrations.
  • RNA from treated and untreated SH-SY5Y cells was extracted by with Trizol (Invitrogen).
  • PMP22 gene expression was analyzed by using a one-step RT-PCR kit (Qiagen), whereby the extracted RNA was mixed with a PMP22 gene specific primer set of SEQ ID NOS: 1 and 2, and a real time-PCR (RT-PCR) was performed to confirm the degree of mRNA expression.
  • FIG. 2 illustrates the results of ⁇ -PMP22 gene expression of SH-SY5Y cells in the presence of DDS measured by RT-PCR at the cDNA level. As shown in FIG. 2 , expression of PMP22 mRNA did not show a significant difference according to a DDS concentration.
  • DDS controls and reduces expression of PMP22 by regulation at a protein level.
  • DDS is deemed as being involved in a decomposition pathway of PMP22 and promoting PMP22 decomposition, but the scope of embodiments is not limited to a specific mechanism.
  • FIGS. 3A and 3B illustrate the results of ⁇ -PMP22 gene expression of SH-SY5Y cells in the presence of DDS, SSZ, and MADDS measured by Western blot.
  • FIG. 3A is an image of the Western blot
  • FIG. 3B illustrates the results in a graph of intensities or densities of each band of the Western blot image measured with the Image J program.
  • FIGS. 3A and 3B illustrate the results of ⁇ -PMP22 gene expression of SH-SY5Y cells in the presence of DDS, SSZ, and MADDS measured by Western blot.
  • FIGS. 4A and 4B illustrate the results of ⁇ -PMP22 gene expression of SH-SY5Y cell strains in the presence of SCM measured by Western blot.
  • FIG. 4A is an image of the Western blot
  • FIG. 4B illustrates the results in a graph of intensities or densities of each band of the Western blot image measured by using the Image J program.
  • "Mock” represents a non-treatment group
  • "DMSO” represents a control group which is treated with the solvent DMSO, instead of SCM
  • SCM represents a test performed with SCM added to DMSO at a predetermined concentration.
  • FIGS. 4A and 4B when SCM was added, the amount of the PMP22 protein decreased compared to that of the control group.
  • FIGS. 5A and FIG. 5B illustrate the results of ⁇ -PMP22 gene expression of SH-SY5Y cells in the presence of AA, DDS, and MADDS measured by Western blot.
  • FIG. 5A is an image of the Western blot
  • FIG. 5B illustrates the results in a graph of intensities or densities of each band of the Western blot image measured by using the Image J program.
  • FIGS. 5A and FIG. 5B illustrate the results of ⁇ -PMP22 gene expression of SH-SY5Y cells in the presence of AA, DDS, and MADDS measured by Western blot.
  • FIG. 5A is an image of the Western blot
  • FIG. 5B illustrates the results in a graph of intensities or densities of each band of the Western blot image measured by using the Image J program.
  • “Mock” represents a non-treatment group
  • "DMSO” represents a control group which is treated with the solvent DMSO, instead of AA, DDS, or MADDS
  • "AA", "DDS”, and “MADDS” represent a test performed with AA, DDS, and MADDS that are each added to DMSO at a respective predetermined concentration.
  • FIGS. 5A and 5B when DDS and MADDS were each added, the amount of the PMP22 protein significantly decreased compared to those of a negative control group and a positive control group, in which AA was added.
  • NTR nitroreductase
  • NfsB toxic gene was myelin-specifically expressed in the genetically engineered zebrafish.
  • the added Mtz matrix was removed from the culture medium, and the genetically engineered zebrafish were cultured in culture medium free of Mtz for 1 week followed by a recovery period.
  • This study confirmed that remyelination of the demyelinated central nervous system and peripheral nervous system occurred naturally, and an effect of DDS, MADDS, SSZ, and SCM drugs on the promotion of remyelination was confirmed.
  • 100 zebrafish were incubated in egg water or an embryo medium (EM) (which includes 15 mM NaCl, 0.5 mM KCI, 1 mM CaCl 2 , 1 mM MgSO 4 , 0.15 mM KH 2 PO 4 , 0.05 mM NH 2 PO 4 , and 0.7 mM NaHCO 3 ) at 28.5°C in 1 L of water in a water tank for 4.5 dpf (days post-fertilization) from birth date, and then, 10 mM of MTZ (Sigma) dissolved in an EM including 0.2% DMSO was added thereto for 36 hours of demyelination.
  • EM embryo medium
  • Each of the zebrafish was transferred to a well with each of the drugs in a 96-well plate and was incubated at 28.5°C. Some of the zebrafish were remyelinated by removing MTZ in the EM by washing the zebrafish with a new EM three times after 6 dpf. 10 uM of DDS, MADDS, SSZ, and SCM were each added to the remaining zebrafish and incubated under the same conditions. A control group was incubated under the same condition except that 0.2% DMSO was added instead of adding MTZ.
  • FIG. 6 is an image of a zebrafish (Mbp:gal4;;UAS:nfsB (NTR, toxin);;UAS:gfp), taken by a confocal laser microscope (Olympus).
  • a white dashed line box is a part to be monitored for remyelination in myelin of the central nervous system and the peripheral nervous system.
  • FIG. 7 shows images of the central nervous system and peripheral nervous system of zebrafish that are each respectively treated with MZT, DDS, MADDS, SSZ, and SCM, where the images are taken by a confocal laser microscope (Olympus).
  • CNS denotes the central nervous system
  • PNS denotes the peripheral nervous system.
  • the "CNS” and "PNS” were the measured myelin sites in the white dashed line region.
  • the white dashed line shows a region where fluorescence disappeared due to demyelination and where change in myelination occurred, compared to that of the control group.
  • a fluorescent intensity is proportional to a degree of myelination.
  • FIGS. 8A and 8B illustrate the results of fluorescent intensity with respect to the same area of myelination site of CNS and PNS. As shown in FIGS. 8A and 8B , myelination at CNS ( FIG. 8A ) and PNS ( FIG. 8B ) significantly increased, compared to that in the control group.
  • Tr-J mice Trembler-J mice
  • the Tr-J mouse has a missense mutation in the murine peripheral myelin protein-22 gene (Pmp22). Pmp22 mutations are believed to cause the neuropathies of Charcot-Marie-Tooth disease in humans ( Nature 356, 241-244 (19 March 1992 ); doi:10.1038/356241a0).
  • Two month old heterozygous Tr J mice in the C57BL/6J background were obtained from Jackson Laboratories (Bar Harbor, ME). Matings between Tr-J heterozygous females and males in the C57BL/6 genetic background were implemented to generate Tr-J heterozygous and wild-type (WT) controls.
  • mice Male and female C57BL/6J background mice were obtained from Jackson Laboratories (Bar Harbor, ME) and maintained at 12-hr dark/light cycles in air controlled rooms, with free access to food and water. All efforts were made to minimize animal suffering from pain and discomfort and to reduce the number of animals used. After 1 week adaptation to laboratory conditions, the animals were randomly assigned to experimental groups consisting of 4-5 mice.
  • mice were placed on a rotating rod (30 mm in diameter) spinning at 4 rpm after 2 months treatment. The mice were first placed on the rubber-covered rod and left for 30 sec on the rod without rotation. Once stabilized, mice were subjected to an incrementally increasing speed of 1 rpm per 8 s. Each animal underwent three trials. The average length of time that the mice managed to remain on the rod was recorded.
  • sciatic nerves were harvested from mice (WT+/- 50 mg/kg sulfasalazine and Trembler J+/- 50 mg/kg sulfasalazine). Nerves were fixed in 2% (w/v) glutaraldehyde in 0.1 M phosphate buffer (pH 7.4) for 4 h, followed by washing with 0.1 M phosphate buffer. After immersion in 8% (w/v) sucrose solution, samples were embedded in Eponate (Ted Pella, CA). Each section was stained with toluidine blue. Sample sections were evaluated using light microscopy.
  • mice In order to examine whether sulfasalazine has an effect on twitching and tetanizing when electric stimulation is applied to muscle, the isometric force of muscle was measured. Specifically, in order to separate muscle from 2-month treated mice (Trembler J+/- 50 mg/kg sulfasalazine), the mice were anesthetized by injection with sodium pentobarbital (100 mg/kg body weight).
  • One end of the tendon was anchored to a tissue bath, which was filled with Ringer's solution, and to which oxygen was smoothly supplied, and the other end was anchored to a isometric force transducer (Model FT03 Grass instruments, West Warwick, RI).
  • the twitch and tetanus of the muscle were adjusted by the intensity of electric stimulation.
  • the muscle was stabilized in Ringer's solution for 10 minutes, and then an experiment for muscle contraction function was carried out.
  • FIG. 9 illustrates the Rotarod test results for sulfasalazine-treated and placebo-treated Tr-J mice (CMT mouse model).
  • SSZ-50 mg/kg represents the results for Tr-J SSZ treated mice (50 mg/kg SSZ per day for 2 months)
  • vehicle represents the results from placebo-treated Tr-J mice (treated daily for 2 months).
  • the time on rod was significantly increased for the SSZ-treated Tr-J mice compared to the placebo-treated Tr-J mice, while the time on rod was decreased for the SSZ-treated WT mice compared to the placebo-treated WT mice. This indicates that SSZ improves the locomotor capacity of the Tr-J mice (CMT mouse model).
  • FIG. 10A-C represent the microscopic image (A), definition of g-ratio (B), and g-ratio (C) of the sciatic nerve of a sulfasalazine-treated Tr-J mouse.
  • the mouse sciatic nerve was stained with toluidine blue, which stains the myelin of sciatic nerve blue.
  • FIG. 10A indicates that number of myelinated axons in the sulfasalazine-treated Tr-J mouse sciatic nerve was significantly increased compared to the vehicle-treated Tr-J mouse.
  • FIG. 10C represents the average g-ratio (illustrated in Fig.
  • FIG. 11A and 11B represent twitch and tetanus contraction in Soleus tendon of SSZ treated Tr-J mouse. As shown in FIG. 11A and 11B , twitch and tetanus contraction were significantly increased in SSZ treated Tr-J mice compared to respective placebo-treated mice. This indicates that SSZ improves the muscle function of the Tr-J mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP15193093.0A 2014-11-05 2015-11-05 Sulfasalazine pour son utilisation dans le traitement de la maladie de charcot marie tooth Active EP3017818B1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020140153180A KR102364840B1 (ko) 2014-11-05 2014-11-05 신경세포의 탈수초화와 연관된 질환을 치료하기 위한 약학적 조성물 및 그를 이용하는 방법

Publications (2)

Publication Number Publication Date
EP3017818A1 true EP3017818A1 (fr) 2016-05-11
EP3017818B1 EP3017818B1 (fr) 2018-07-18

Family

ID=54365120

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15193093.0A Active EP3017818B1 (fr) 2014-11-05 2015-11-05 Sulfasalazine pour son utilisation dans le traitement de la maladie de charcot marie tooth

Country Status (4)

Country Link
US (1) US9820997B2 (fr)
EP (1) EP3017818B1 (fr)
KR (1) KR102364840B1 (fr)
CN (1) CN105560256B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102526648B1 (ko) * 2015-08-21 2023-04-27 삼성전자주식회사 2,5-디히드록시벤젠술폰산을 포함하는 신경세포의 수초화를 촉진하기 위한 조성물 및 그의 용도
KR101983850B1 (ko) 2017-11-06 2019-05-29 동아대학교 산학협력단 탈미엘린화 유발 신경계 질환의 예방 또는 치료용 의약 조성물 및 건강기능식품
WO2023182288A1 (fr) * 2022-03-22 2023-09-28 国立大学法人京都大学 Médicament pour le traitement ou la prévention de la maladie de charcot-marie-tooth

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2396145A (en) 1940-12-14 1946-03-05 Pharmscia Ab Heterocyclic sulphonamido azo compounds
US20030191191A1 (en) * 1995-07-31 2003-10-09 Blume Cheryl D. Methods for preventing and treating peripheral neuropathy by administering desmethylselegiline delivery compositions
US20080293737A1 (en) * 2007-05-25 2008-11-27 Esther Martinborough Ion channel modulators and methods of use
WO2013152039A1 (fr) * 2012-04-02 2013-10-10 The Trustees Of Columbia University In The City Of New York Composés, compositions, et procédés pour moduler la ferroptose et traiter des troubles excitotoxiques
US20140221321A1 (en) * 2013-02-01 2014-08-07 Glialogix, Inc. Compositions and Methods for the Treatment of Neurodegenerative and Other Diseases
WO2015028659A1 (fr) * 2013-08-30 2015-03-05 Pharnext Composition contenant de la torasemide et du baclofène, pour le traitement de troubles neurologiques

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100417623B1 (ko) * 2000-03-28 2004-02-05 주식회사 뉴로테크 뇌질환 예방 및 치료용 조성물
CN100531799C (zh) * 2000-07-19 2009-08-26 西北大学 增强抗感染剂作用的制剂和方法
KR20050114212A (ko) 2003-01-24 2005-12-05 엘란 파마슈티칼스, 인크. 수초재생제의 투여에 의한 탈수초성 질환 및 마비의 치료및 조성물
KR100532453B1 (ko) 2003-07-23 2005-11-30 삼성전자주식회사 로우 리던던시 효율을 향상시킬 수 있는 로우 리페어 방법및 이를 이용하는 반도체 메모리장치
KR100839512B1 (ko) * 2004-07-02 2008-06-19 주식회사 코오롱 설파제를 디아조화체로 하는 산성 항균 염료 및 그를이용한 항균 섬유
KR100821900B1 (ko) * 2005-09-15 2008-04-16 주식회사 코오롱 항균 산성 염료와 그의 제조 방법 및 그를 이용한 항균섬유
JP2010503679A (ja) * 2006-09-15 2010-02-04 シェーリング コーポレイション 疼痛および脂質代謝障害を処置する際に有用なアゼチジン誘導体およびアゼチドン誘導体
CA2961187A1 (fr) * 2014-09-16 2016-03-24 Teva Pharmaceuticals Industries Ltd. Traitement de maladies neurodegenerative avec une combinaison de laquinimod et de fingolimod
EP3000464B1 (fr) 2014-09-26 2020-05-06 Daegu Gyeongbuk Institute Of Science and Technology Composition comprenant du farnésol et son utilisation
KR20160047318A (ko) 2014-10-22 2016-05-02 삼성전자주식회사 다프손을 포함하는, 개체의 부위에서 혈관신생을 자극시키기 위한 조성물 및 그의 용도

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2396145A (en) 1940-12-14 1946-03-05 Pharmscia Ab Heterocyclic sulphonamido azo compounds
US20030191191A1 (en) * 1995-07-31 2003-10-09 Blume Cheryl D. Methods for preventing and treating peripheral neuropathy by administering desmethylselegiline delivery compositions
US20080293737A1 (en) * 2007-05-25 2008-11-27 Esther Martinborough Ion channel modulators and methods of use
WO2013152039A1 (fr) * 2012-04-02 2013-10-10 The Trustees Of Columbia University In The City Of New York Composés, compositions, et procédés pour moduler la ferroptose et traiter des troubles excitotoxiques
US20140221321A1 (en) * 2013-02-01 2014-08-07 Glialogix, Inc. Compositions and Methods for the Treatment of Neurodegenerative and Other Diseases
WO2015028659A1 (fr) * 2013-08-30 2015-03-05 Pharnext Composition contenant de la torasemide et du baclofène, pour le traitement de troubles neurologiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D. W. PATY: "The Mayo Clinic-Canadian cooperative trial of sulfasalazine in active multiple sclerosis", NEUROLOGY, vol. 53, no. 2, 1 July 1999 (1999-07-01), pages 437 - 437, XP055117758, ISSN: 0028-3878, DOI: 10.1212/WNL.53.2.437 *
NATURE, vol. 356, 19 March 1992 (1992-03-19), pages 241 - 244
SUHYUN KIM: "Promotion of Remyelination by Sulfasalazine in a Transgenic Zebrafish Model of Demyelination", MOLECULES AND CELLS, vol. 38, no. 11, 6 November 2015 (2015-11-06), KR, pages 1013 - 1021, XP055251015, ISSN: 1016-8478, DOI: 10.14348/molcells.2015.0246 *

Also Published As

Publication number Publication date
KR20160053711A (ko) 2016-05-13
CN105560256B (zh) 2019-12-27
CN105560256A (zh) 2016-05-11
US9820997B2 (en) 2017-11-21
EP3017818B1 (fr) 2018-07-18
US20160120884A1 (en) 2016-05-05
KR102364840B1 (ko) 2022-02-18

Similar Documents

Publication Publication Date Title
JP6879980B2 (ja) ウロリチンまたはその前駆体の投与によるオートファジーの増強または寿命の延長
JP6876047B2 (ja) ミトコンドリアの活性酸素種（ｒｏｓ）産生に関連する疾患の治療のための化合物
Komiya et al. TRPM channels and magnesium in early embryonic development
TW200918542A (en) Sirtuin modulating compounds
JP2010528016A (ja) 細胞を刺激するための方法および組成物
JP2012529432A (ja) アミノピロリジノン誘導体及びその使用
EP3017818B1 (fr) Sulfasalazine pour son utilisation dans le traitement de la maladie de charcot marie tooth
CA2906194A1 (fr) Derives de benzimidazole et leurs utilisations
CN106659701B (zh) 用于治疗年龄相关性症状和疾病的酮基丁酸酯化合物和组合物
JP2018524392A (ja) 新規治療用化合物及びその治療における使用
EP3004058B1 (fr) Composes inhibiteurs de l&#39;acetylcholinesterase et agonistes des recepteurs serotoninergiques 5ht4, a effet promnesiant, leurs procedes de preparation et compositions pharmaceutiques les contenant
US11458146B2 (en) Compositions and methods for the treatment of myelin related and inflammation related diseases or disorders
JP2021105061A (ja) アミロイド線維形成の抑制又は阻害剤
US11723907B2 (en) Anti-aging compounds
KR102526648B1 (ko) 2,5-디히드록시벤젠술폰산을 포함하는 신경세포의 수초화를 촉진하기 위한 조성물 및 그의 용도
JP7280470B2 (ja) 特定アミノ酸またはアミノ酸様物質による低酸素応答制御
WO2019195742A1 (fr) Compositions et méthodes permettant d&#39;augmenter la remyélinisation
US20230174988A1 (en) Methods for inducing bile acid sulfotransferase sult2a for treating metabolic disorders
JP7072260B2 (ja) マックル・ウェルズ症候群の治療用医薬組成物
TW201738214A (zh) 用於治療中風的環烯醚萜苷類化合物，其醫藥組合物及其用途
WO2018043476A1 (fr) Agent thérapeutique pour la sclérose latérale amyotrophique et composition pour traitement
Kazokaitė Investigation of human carbonic anhydrase VI and IX inhibitor efficacy and toxicity
JP2023502791A (ja) 大環状パンテテイン誘導体およびその用途
JP2019199438A (ja) プロテオリピドタンパク質１の構造不全の改善剤、及びプロテオリピドタンパク質１の構造不全に起因する疾患又は症状の予防又は治療薬、並びにそれらの用途
Santos The role of N-terminal phosphorylation on Huntingtin oligomerization, aggregation and toxicity

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

17P Request for examination filed

Effective date: 20161111

RBV Designated contracting states (corrected)

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

R17P Request for examination filed (corrected)

Effective date: 20161111

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20180216

RIN1 Information on inventor provided before grant (corrected)

Inventor name: LEE, YUNIL

Inventor name: PARK, SANGCHUL

Inventor name: CHO, SUNGCHUN

Inventor name: CHANG, KIYOUNG

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1018631

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180815

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602015013646

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20180718

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1018631

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181019

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181018

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181118

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181018

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602015013646

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

26N No opposition filed

Effective date: 20190423

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181105

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20181130

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181130

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181105

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181105

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180718

Ref country code: MK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180718

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20151105

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230530

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20231019

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20231024

Year of fee payment: 9

Ref country code: DE

Payment date: 20231024

Year of fee payment: 9